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Female resistance to pneumonia identifies lung macrophage nitric oxide synthase-3 as a therapeutic target.

Yang Z, Huang YC, Koziel H, de Crom R, Ruetten H, Wohlfart P, Thomsen RW, Kahlert JA, Sørensen HT, Jozefowski S, Colby A, Kobzik L - Elife (2014)

Bottom Line: Epidemiologic data show decreased hospitalization for pneumonia in women receiving estrogen or statins (known to activate NOS3).Pharmacologic targeting of NOS3 with statins or another small-molecule compound (AVE3085) enhanced macrophage bacterial killing, improved bacterial clearance, and increased host survival in both primary and secondary (post-influenza) pneumonia.The data identify a novel mechanism for host defense via NOS3 and suggest a potential therapeutic strategy to reduce secondary bacterial pneumonia after influenza.

View Article: PubMed Central - PubMed

Affiliation: Department of Environmental Health, Harvard School of Public Health, Boston, United States.

ABSTRACT
To identify new approaches to enhance innate immunity to bacterial pneumonia, we investigated the natural experiment of gender differences in resistance to infections. Female and estrogen-treated male mice show greater resistance to pneumococcal pneumonia, seen as greater bacterial clearance, diminished lung inflammation, and better survival. In vitro, lung macrophages from female mice and humans show better killing of ingested bacteria. Inhibitors and genetically altered mice identify a critical role for estrogen-mediated activation of lung macrophage nitric oxide synthase-3 (NOS3). Epidemiologic data show decreased hospitalization for pneumonia in women receiving estrogen or statins (known to activate NOS3). Pharmacologic targeting of NOS3 with statins or another small-molecule compound (AVE3085) enhanced macrophage bacterial killing, improved bacterial clearance, and increased host survival in both primary and secondary (post-influenza) pneumonia. The data identify a novel mechanism for host defense via NOS3 and suggest a potential therapeutic strategy to reduce secondary bacterial pneumonia after influenza.

No MeSH data available.


Related in: MedlinePlus

Female alveolar macrophages show better killing of ingested bacteria.Binding (A) and internalization (B) of S. pneumoniae in normal male and female AMs is similar. Female AMs kill more internalized bacteria than male AMs in assays using pneumococci (C) (n > 11, * = p < 0.01), S. aureus (D) or E. coli (E), (n > 3, * = p < 0.01). (F). Normal human female AMs also show greater killing of internalized pneumococci, (n > 5, * = p < 0.01).DOI:http://dx.doi.org/10.7554/eLife.03711.005
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fig2: Female alveolar macrophages show better killing of ingested bacteria.Binding (A) and internalization (B) of S. pneumoniae in normal male and female AMs is similar. Female AMs kill more internalized bacteria than male AMs in assays using pneumococci (C) (n > 11, * = p < 0.01), S. aureus (D) or E. coli (E), (n > 3, * = p < 0.01). (F). Normal human female AMs also show greater killing of internalized pneumococci, (n > 5, * = p < 0.01).DOI:http://dx.doi.org/10.7554/eLife.03711.005

Mentions: To compare the innate antibacterial function of alveolar macrophages from both genders, we measured phagocytosis and killing of pneumococci in vitro by AMs from normal mice and humans. Analysis of bacterial binding and internalization showed no differences between male and female murine AMs (Figure 2A,B; similar data with human AMs not shown). In contrast, killing of internalized bacteria was greater in female AMs than male AMs in mouse samples challenged with S. pneumoniae, as well as with other lung pathogens Staphylococcus aureus, and Escherichia Coli (Figure 2C–E). Similarly, normal human female AMs showed greater killing of ingested pneumococci than their male counterparts (Figure 2F).10.7554/eLife.03711.005Figure 2.Female alveolar macrophages show better killing of ingested bacteria.


Female resistance to pneumonia identifies lung macrophage nitric oxide synthase-3 as a therapeutic target.

Yang Z, Huang YC, Koziel H, de Crom R, Ruetten H, Wohlfart P, Thomsen RW, Kahlert JA, Sørensen HT, Jozefowski S, Colby A, Kobzik L - Elife (2014)

Female alveolar macrophages show better killing of ingested bacteria.Binding (A) and internalization (B) of S. pneumoniae in normal male and female AMs is similar. Female AMs kill more internalized bacteria than male AMs in assays using pneumococci (C) (n > 11, * = p < 0.01), S. aureus (D) or E. coli (E), (n > 3, * = p < 0.01). (F). Normal human female AMs also show greater killing of internalized pneumococci, (n > 5, * = p < 0.01).DOI:http://dx.doi.org/10.7554/eLife.03711.005
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4215537&req=5

fig2: Female alveolar macrophages show better killing of ingested bacteria.Binding (A) and internalization (B) of S. pneumoniae in normal male and female AMs is similar. Female AMs kill more internalized bacteria than male AMs in assays using pneumococci (C) (n > 11, * = p < 0.01), S. aureus (D) or E. coli (E), (n > 3, * = p < 0.01). (F). Normal human female AMs also show greater killing of internalized pneumococci, (n > 5, * = p < 0.01).DOI:http://dx.doi.org/10.7554/eLife.03711.005
Mentions: To compare the innate antibacterial function of alveolar macrophages from both genders, we measured phagocytosis and killing of pneumococci in vitro by AMs from normal mice and humans. Analysis of bacterial binding and internalization showed no differences between male and female murine AMs (Figure 2A,B; similar data with human AMs not shown). In contrast, killing of internalized bacteria was greater in female AMs than male AMs in mouse samples challenged with S. pneumoniae, as well as with other lung pathogens Staphylococcus aureus, and Escherichia Coli (Figure 2C–E). Similarly, normal human female AMs showed greater killing of ingested pneumococci than their male counterparts (Figure 2F).10.7554/eLife.03711.005Figure 2.Female alveolar macrophages show better killing of ingested bacteria.

Bottom Line: Epidemiologic data show decreased hospitalization for pneumonia in women receiving estrogen or statins (known to activate NOS3).Pharmacologic targeting of NOS3 with statins or another small-molecule compound (AVE3085) enhanced macrophage bacterial killing, improved bacterial clearance, and increased host survival in both primary and secondary (post-influenza) pneumonia.The data identify a novel mechanism for host defense via NOS3 and suggest a potential therapeutic strategy to reduce secondary bacterial pneumonia after influenza.

View Article: PubMed Central - PubMed

Affiliation: Department of Environmental Health, Harvard School of Public Health, Boston, United States.

ABSTRACT
To identify new approaches to enhance innate immunity to bacterial pneumonia, we investigated the natural experiment of gender differences in resistance to infections. Female and estrogen-treated male mice show greater resistance to pneumococcal pneumonia, seen as greater bacterial clearance, diminished lung inflammation, and better survival. In vitro, lung macrophages from female mice and humans show better killing of ingested bacteria. Inhibitors and genetically altered mice identify a critical role for estrogen-mediated activation of lung macrophage nitric oxide synthase-3 (NOS3). Epidemiologic data show decreased hospitalization for pneumonia in women receiving estrogen or statins (known to activate NOS3). Pharmacologic targeting of NOS3 with statins or another small-molecule compound (AVE3085) enhanced macrophage bacterial killing, improved bacterial clearance, and increased host survival in both primary and secondary (post-influenza) pneumonia. The data identify a novel mechanism for host defense via NOS3 and suggest a potential therapeutic strategy to reduce secondary bacterial pneumonia after influenza.

No MeSH data available.


Related in: MedlinePlus